US 6,087,346 AGranted

Sigma receptor ligands and the use thereof

AssigneesCambridge NeuroScience, Inc., Virginia Commonwealth University

InventorsRichard A. Glennon, James B. Fischer

Life of this patent

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Abstract

The invention relates to methods for the treatment of central nervous system disorders, neurological disorders, gastrointestinal disorders, drug abuse, angina, migraine, hypertension and depression by administering a pharmaceutical composition comprising an effective amount of certain sigma receptor ligands to a patient in need of such treatment. The invention further relates to novel sigma receptor ligands having high binding to the sigma receptor and pharmaceutical compositions thereof.

Claims17

Dependent claims

A method of treating a human being suffering from, drug abuse, gastrointestinal disorder, hypertension, migraine, angina or depressionwhich comprises administering to said human a therapeutically effective amount of a compound of Formula I:

##STR61## wherein m is 0 or 1;
n is 0, 1, 2, 3, 4, 5, or 6;
R.sub.1 is selected from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, indane, substituted indane, tetralin, substituted tetralin, benzocycloheptane, substituted benzocycloheptane, wherein the substituents are selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxy, C.sub.1-6 alkyl, trifluoromethyl;
or wherein R.sub.1 is:
##STR62## R.sub.2 and R.sub.3 are each independently selected from hydrogen, hydroxy, C.sub.1-6 alkyl, or together two R.sub.2 and R.sub.3 groups may be a double bond between adjacent carbon atoms;
R.sub.4 is hydrogen, C.sub.1-6 alkyl, substituted C.sub.1-6 alkyl, benzyl, C.sub.2-6 alkaryl, benzoyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, indane, substituted indane, tetralin, substituted tetralin, benzocycloheptane, substituted benzocycloheptane, wherein the substituents are selected from halogen, hydroxy, C.sub.1-6 alkyl;
or wherein R.sub.4 is:
##STR63## and pharmaceutically acceptable salts thereof.

5 more elements

A method of treating a human being suffering from a central nervous sytem disorder, drug abuse, gastrointestinal disorder, hypertension, migraine, angina or depression, which comprises administering to said human a therapeutically effective amount of one or more compounds selected from the group consisting of:

N-methyl-N-(5-phenylpentyl)-2-phenylethylamine;
N-methyl-N-(5-phenylpentyl)amine;
N-(5-phenylpentyl)-N-(2-phenylethyl)amine;
N-(5-phenylpentyl)-pyrrolidine;
N-(2-phenylethyl)-N-(l-pyrrolidinoethyl)amine;
N,N-(diphenylethyl)-N-(1-pyrrolidinoethyl)amine;
N-methyl-N-(5-(3-trifluorophenyl)pentyl)-N-(2-phenylethyl)amine;
N-methyl(5-phenylpentyl)-N-(2-(3-trifluoromethylphenyl)ethyl)amine;
N-methyl-(5-(3-trifluoromethylphenyl)-5-pentanon-1-yl)-(2-phenylethyl)amine
N-methyl-(5-(3-trifluoromethylphenyl)-5-1-pentanol)-(2-phenylethyl)amine;
N-(2-(4-phenylsulfonic acid)ethyl-5-pentylamine;
N-diethyl-5-(1,1-diphenylpentyl)amine;
N-diethyl-5-phenyl-5-pentanon-1-yl)amine;
N-diethyl-5-(phenylpentyl)amine;
N-2-(1-phenylpropyl)-5-(phenylpentyl)amine;
N-2-(1-phenylpropyl)-4-(phenylbutyl)amine;
N-methyl-2-(1-phenylpropyl)-2-(phenylethyl)amine;
N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-4-chlorophenyl)piperidine;
N-(5-(3,4-dichlorophenyl)-5-pentanon-1-yl)-4-chlorophenyl)piperidine;
N-methyl-4-(diphenylmethoxy)piperidine;
N-(5-(cyclopentyl)-5-pentanon-1-yl)piperidine;
N-(5-phenyl-5-pentanon-1-yl)piperidine;
N-5-(4-chlorophenyl)-5-pentanon-1-yl)piperidine;
N-5-(3-methoxyphenyl-5-pentyl)piperidine;
N-5-(3,4-methylenedioxyphenyl)piperidine;
N-2-(4-biphenyl)ethylpiperidine;
N-(4-phenylbutyl)-4-benzylpiperidine;
N-benzyl-4-(4-phenylbutyl)piperidine;
N-(4-phenylbutyl)-4-benzoylpiperidine;
N-(4-phenylbutyl)-4-(hydroxyphenylmethyl)piperidine;
N-4-(phenylbutyl)-4-(diphenylmethyl)piperidine;
N-phenyl-4-(3-benzoylaminopropyl)piperazine;
N-phenyl-4-(3-(p-chlorobenzoyl)aminopropyl)piperazine;
N-phenyl-4-(3-(p-methoxybenzoyl)aminopropyl)piperazine;
N-phenyl-4-(3-benzylaminopropyl)piperazine;
and N-phenyl-4-(3-benzyl-(N'-acetyl)-aminopropyl)piperazine;
and pharmaceutically acceptable salts thereof.

34 more elements

A method of treating a human being suffering from drug abuse, gastrointestinal disorder, hypertension, migraine, angina or depression which comprises administering to said human a therapeutically effective amount of one or more compounds selected from the group consisting of:

N-methyl-N-(5-phenylpentyl)-2-phenylethylamine;
N-methyl-N-(5-phenylpentyl)amine;
N-(5-phenylpentyl)-N-(2-phenylethyl)amine;
N-(5-phenylpentyl)pyrrolidine;
N-(2-phenylethyl)-N-(1-pyrrolidino)amine;
N,N,-(di-2-phenylethyl)-N-(1-pyrrolidinoethyl)amine;
N-methyl-N-(5-(3-trifluorophenyl)pentyl)-N-(2-phenylethyl)amine;
N-methyl(5-phenylpentyl)-N-(2-(3-trifluoromethylphenyl)ethyl)amine;
N-methyl-(5-(3-trifluoromethylphenyl)-5-pentanon-1-yl)-(2-phenylethyl)amine ;
N-methyl-(5-(3-trifluoromethylphenyl)-5-1-pentanol)-(2-phenylethyl)amine;
N-(2-(4-phenylsulfonic acid)ethyl-5-pentylamine;
N-diethyl-5-(1,1-diphenylpentyl)amine;
N-diethyl-5-phenyl-5-pentanon-1-yl)amine;
N-diethyl-5-(phenylpentyl)amine;
N-2-(1-phenylpropyl)-5-(phenylpentyl)amine;
N-2-(1-phenylpropyl)-4-(phenylbutyl)amine;
N-methyl-2-(1-phenylpropyl)-2-(phenylethyl)amine;
N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-4-chlorophenyl)piperidine;
N-(5-(3,4-dichlorophenyl)-5-pentanon-1-yl)-4-chlorophenyl)piperidine;
N-methyl-4-(diphenylmethoxy)piperidine;
N-(5-(cyclopentyl)-5-pentanon-1-yl)piperidine;
N-(5-phenyl-5-pentanon-1-yl)piperidine;
N-5-(4-chlorophenyl)-5-pentanon-1-yl)piperidine;
N-5-(3-methoxyphenyl-5-pentyl)piperidine;
N-5-(3,4-methylenedioxyphenyl)piperidine;
N-2-(4-biphenyl)ethyl piperidine;
N-(4-phenylbutyl)-4-benzylpiperidine;
N-benzyl-4-(4-phenylbutyl)piperidine;
N-(4-phenylbutyl)-4-benzoylpiperidine;
N-(4-phenylbutyl)-4-(hydroxyphenylmethyl)piperidine;
N-4-(phenylbutyl)-4-(diphenylmethyl)piperidine;
N-phenyl-4-(3-benzoylaminopropyl)piperazine;
N-phenyl-4-(3-(p-chlorobenzoyl)aminopropyl)piperazine;
N-phenyl-4-(3-(p-methoxybenzoyl)aminopropyl)piperazine;
N-phenyl-4-(3-benzylaminopropyl)piperazine;
and N-phenyl-4-(3-benzyl-(N'-acetyl)-aminopropyl)piperazine;
and pharmaceutically acceptable salts of said compounds.

34 more elements

A method for treating a neurological disorder comprising administering to a subject suffering from or susceptible to such a disorder an effective amount of a compound of the following formula:

##STR69## wherein m is 0 or 1;
n is 0, 1, 2, 3, 4, 5, or 6;
R.sub.1 is selected from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl, substituted phenyl, wherein the substituents are selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxy, C.sub.1-6 alkyl, trifluoromethyl;
or wherein R.sub.1 is:
##STR70## R.sub.2 and R.sub.3 are each independently selected from hydrogen, hydroxy, C.sub.1-6 alkyl, or together two R.sub.2 and R.sub.3 groups may be a double bond between adjacent carbon atoms;
R.sub.4 is hydrogen, C.sub.1-6 alkyl, substituted C.sub.1-6 alkyl, benzyl, C.sub.2-6 alkaryl, benzoyl, phenyl, substituted phenyl, wherein the substituents are selected from halogen, hydroxy, C.sub.1-6 alkyl;
or wherein R.sub.4 is:
##STR71## and pharmaceutically acceptable salts thereof.

5 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/564,362Filed 21 Feb 1996 · continuation in part
Priority: 23 Jun 1993
Granted: 11 Jul 2000
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 317/58
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring: radicals…
C07C 211/27
Of an unsaturated carbon skeleton containing at least one six-membered aromatic ring: having amino groups linked to the six-membered aromatic ring…
C07C 211/28
Of an unsaturated carbon skeleton containing at least one six-membered aromatic ring: having amino groups linked to the six-membered aromatic ring…
C07C 211/29
Of an unsaturated carbon skeleton containing at least one six-membered aromatic ring: the carbon skeleton being further substituted by halogen…

Family

Serial082,406Parent of this continuation-in-part · filed 23 Jun 1993
PCTUS9407121Parent of this continuation · filed 25 Jun 1994
US 6,087,346 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

08/564,362Filed 21 Feb 1996 · continuation in part

Priority

23 Jun 1993

Granted

11 Jul 2000

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 317/58
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring: radicals…
C07C 211/27
Of an unsaturated carbon skeleton containing at least one six-membered aromatic ring: having amino groups linked to the six-membered aromatic ring…
C07C 211/28
Of an unsaturated carbon skeleton containing at least one six-membered aromatic ring: having amino groups linked to the six-membered aromatic ring…
C07C 211/29
Of an unsaturated carbon skeleton containing at least one six-membered aromatic ring: the carbon skeleton being further substituted by halogen…